In Utero Infection: Child Health and Neurodevelopment

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DESCRIPTION (provided by applicant): Preterm birth is the highest risk factor for cerebral palsy, other adverse neurological outcomes (such as blindness deafness, and mental retardation), and long-term adverse child health outcomes accounting for up to 50% of these adverse sequelae. Most of this morbidity is concentrated among the subset of preterm births that deliver at less than 32 weeks' gestation. Because of the increasing rate of preterm birth in the United States and the increased survival of infants delivered at the earlier gestational ages, the incidence of adverse long-term sequelae is rising. It is now well established that clinically silent upper genital tract intrauterine bacterial infection is strongly associated with a majority of preterm births that occur prior to 32 weeks' gestation. Additionally, emerging data implicate fetal in utero exposure to bacterial infection/inflammation as an independent risk factor for development of cerebral palsy and other adverse health outcomes, it is speculated that proinflammatory cytokine exposure may represent the link to these adverse outcomes. Most of the studies linking infection to adverse neurological outcomes have been limited to short-term neonatal outcomes including markers for subsequent development of cerebral palsy such as periventricular leukomalacia. Long-term follow-up studies in this area are sparse, are largely limited to cerebral palsy as the primary outcome, and provide limited information regarding the maternal/neonatal clinical course. The current literature lacks a longitudinal study with extensive maternal and neonatal clinical, laboratory, microbiological, and histological data on a cohort of maternal-infant pairs on whom long-term outcome evaluation is available including not only cerebral palsy but also other important neurodevelopmental and health outcomes. We hypothesize that in utero exposure to infection/inflammation is associated with increased risk of adverse neurodevelopmental and child health outcomes at age 4-7 years. We propose to test this hypothesis in a cohort of 424 maternal-infant pairs that delivered at our institution between 24 weeks 0 days and 31 weeks 6 days gestation. This cohort has already been studied resulting in an extensive database that includes almost every detail of antepartum, intrapartum, and neonatal clinical data. Also already available from this cohort are histological, microbiological, and biochemical data including umbilical cord blood and neonatal cultures, umbilical cord blood cytokine data, placental histology, and placental cultures. We propose a longitudinal follow-up study of this preterm cohort in order to systematically evaluate the relationship between maternal/fetal infection, fetal exposure to inflammation, neonatal short-term outcomes and ultimate neurodevelopmental outcomes at age 4 to 7 years (Aims 1 and 2) including the potential influence of effect modifiers such as environmental factors and caregiver characteristics (Aim 3). We will also determine if umbilical cord blood markers of neuronal damage are associated with short-term or long-term outcomes (Aim 4) and the strength of association between in utero infection/inflammation, bronchopulmonary dysplasia and long-term indicators of pulmonary dysfunction (Aim 5).